The present application claims priority to provisional U.S. patent application Ser. No. 60/348,594 filed Jan. 15, 2002; provisional U.S. patent application Ser. No. 60/376,040, filed Apr. 26, 2002 and provisional U.S. patent application Ser. No. 60/402,966, filed Aug. 13, 2002. The entire text of each of the above referenced applications is incorporated herein by reference and without disclaimer.
The U.S. Government owns rights in the application pursuant to funding from NIH and National Foundation for Cancer Research through grant number 1R01CA78814.
I. Field of the Invention
The present invention provides novel tricyclic-bis-enone derivatives (TBEs), as well as the process for the preparation of such TBEs, for prevention and/or treatment of cancer, Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotropic lateral sclerosis, rheumatoid arthritis, inflammatory bowel disease, and other diseases whose pathogenesis is believed to involve excessive production of either nitric oxide (NO) or prostaglandins.
II. Description of Related Art
One of the major needs in clinical oncology is the development of effective and safe new agents for chemoprevention. In particular, there is a need for chemopreventative agents targeted at mechanisms known to be involved in the process of carcinogenesis. In recent years, there has been a resurgence of interest in the study of mechanisms of inflammation that relate to carcinogenesis and in the use of such mechanisms as the basis for development of new chemopreventative agents.
The concept that inflammation and carcinogenesis are related phenomena has been the subject of many studies that have attempted to link these two processes in a mechanistic fashion (Sporn and Roberts, 1986; Ohshima and Bartsch, 1994). The enzymes that mediate the constitutive synthesis of NO and prostaglandins from arginine and arachidonate, respectively, have relative little significance for either inflammation or carcinogenesis. In contrast, inducible nitric oxide synthase (iNOS) and inducible cycloxygenase (COX-2) both have critical roles in the response of tissues to injury or infectious agents (Moncada et al., 1991; Nathan and Xie, 1994; Tamir and Tannebaum, 1996). These inducible enzymes are essential components of the inflammatory process, the ultimate repair of injury, and carcinogenesis. While physiological activity of iNOS and COX-2 may provide a definite benefit to the organism, aberrant or excessive expression of either iNOS or COX-2 has been implicated in the pathogenesis of many disease processes, particularly in chronic degeneration of the central nervous system, carcinogenesis, septic shock, cardiomyopathy, and rheumatoid arthritis.
The need for new agents to prevent and treat cancer is readily evident from the continuing high mortality rates for the common forms of epithelial cancer, such as carcinoma of the lung, colon, breast, and prostate. As methods of genetic testing can identify increasing numbers of people who are at high risk for the development of cancers, it becomes increasingly important to discover new pharmacologic agents that can be used interventionally to prevent this outcome, well before the occurrence of malignant invasive disease. The same is true for degenerative diseases, inflammatory diseases and immune diseases that involve increased NO or prostaglandin production. Therefore, the art lacks compounds for the chemoprevention of cancer and the other diseases or conditions described above that can be produced by efficient and cost effective methods and are also easy to administer.